Governmental reports state that prescription drug abuse is the fastest growing drug problem in the United States, and a survey indicated that nearly one-third of people age 12 and above who used drugs illicitly for the first time in 2009 began by the non-medical use of a prescription drug. The problem has been exacerbated by the introduction of controlled-release opioid products that contain higher amounts of their active ingredients, beginning with an oxycodone product that was approved for marketing in 1995. Reports of overdosing and death from prescription pain products, especially the controlled-release oxycodone product, rose sharply in the early 2000s.
Overdose incidence of the opioid dosage forms is summarized in Table 1 below.
TABLE 1Overdose incidence of opioid dosage formsProductOverdose (%)Hydrocodone/APAP-23Immediate ReleaseOxycodone/APAP-11Immediate ReleaseOxycodone Immediate Release7Oxycodone Extended Release4
In January 2013, the U.S. Food and Drug Administration published a draft guidance document for the evaluation and labeling of abuse-resistant opioid products. The guidance states that opioid analgesics can be abused by: swallowing whole in excessive quantities; crushing and swallowing; crushing and inhaling nasally (“snorting”); crushing and smoking; or crushing, dissolving, and injecting. Categories of abuse-resistant formulations were described as:
1. Physical barriers to prevent chewing, crushing, cutting, grating or grinding, and chemical barriers to resist extraction of the active ingredient with common solvents such as water, alcohol, and organic liquids;
2. Agonist/antagonist combinations that interfere with, reduce, or defeat the euphoria associated with abuse;
3. Aversion, by incorporating a substance that produces an unpleasant effect when the dosage form is altered before ingestion, or is ingested in a high dose;
4. Delivery systems that provide abuse resistance through release characteristic design or a mode of administration;
5. Pro-drugs that lack opioid activity until acted upon in the gastrointestinal system; and
6. Combinations of two or more of the foregoing.
The FDA describes the science of abuse deterrence as relatively new and rapidly evolving. A few abuse-resistant opioid products are currently approved for marketing. Some of these products are OxyContin® (oxycodone hydrochloride extended-release tablets), Targiniq® (oxycodone HCL+naloxone HCL), and Embeda® (morphine sulfate and naltrexone hydrochloride). Other products such as Suboxone® and Opana ER® (oxymorphone) also purport to have abuse deterrent properties but do not have a formal claim on the label. The oxycodone hydrochloride extended-release tablets, sold by Purdue Pharma L.P. under the tradename OxyContin® in strengths of 10, 15, 20, 30, 40, 60, and 80 mg, are formulated to have a high hardness to resist crushing, breaking, and dissolution, and also forms a viscous hydrogel in aqueous media that inhibits passage of an extract through a needle.
In general, abusers of opioid drugs do not ingest more than a typical therapeutic dose because the controlled-release formulations do not provide bursts of drug bioavailability to create the desired euphoric sensations. Rather, abuse tends to involve some physical manipulation of a dosage form so that larger amounts of immediately available drug can be taken orally, nasally, or by intravenous injection. For this reason, the OxyContin tablets are formed from a partially molten mixture that contains a high molecular weight polyethylene oxide excipient; the result is a tablet that is not easily powdered and cannot readily be modified to form a solution that is capable of being injected. The very high hardness of this product, however, would not permit reproducible splitting of a dosage form to administer a reduced dose or improve the administration for those having difficulty in swallowing.
A need remains for improved formulations that make it difficult, if not impossible, for individuals to misuse particularly from the standpoints of extracting the drug from multiple doses and ingesting multiple doses. In particular, new formulations are needed which can be used with immediate release and extended release pharmaceutical products. Such formulations, while having abuse-resistant properties, must also allow for the active pharmaceutical ingredient to be soluble in the gastrointestinal tract and have the desired pharmacological activity. In the case of opioids, the pharmacological activity would be an analgesic effect.